Studies on the Different Modes of Action of the Anticoagulant Protease Inhibitors DX-9065a and Argatroban

Nagashima, Hajime

doi:10.1074/jbc.m208222200

Cited by 38 publications

(26 citation statements)

References 14 publications

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“…In an in vitro study that compared the effects of the thrombin inhibitor argatroban and the FXa inhibitor DX-9065a on fibrinolysis, it was demonstrated that the direct inactivation of thrombin by a specific inhibitor is more effective in accelerating fibrinolysis of a clot than the inhibition of FXa (35). The in vitro results were confirmed by in vivo studies using a rat model of microvascular thrombosis.…”

Section: Effect On Fibrinolysismentioning

confidence: 69%

“…Thrombin, in a thrombomodulin-dependent manner, proteolytically activates TAFI to TAFIa which inhibits fibrinolysis by removing the C-terminal lysine and arginine residues from partially degraded fibrin. The direct inactivation of thrombin or the inhibition of its generation might reduce the thrombin-thrombomodulindependent activation of TAFI resulting in an enhanced fibrinolysis (15,34,35).…”

Section: Effect On Fibrinolysismentioning

confidence: 99%

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DX‐9065a, a Direct Inhibitor of Factor Xa

Kaiser

2003

Cardiovascular Drug Reviews

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The synthetic compound DX-9065a represents a low molecular weight, direct, competitive inhibitor of factor Xa (FXa) with a high affinity and selectivity for the enzyme. Under experimental conditions DX-9065a exerts strong anticoagulant actions in vitro and in vivo and is antithrombotically effective in various thrombosis models. It inhibits proliferation of vascular smooth muscle cells in cell culture systems as well as in in vivo models. As a small molecule inhibitor, DX-9065a inactivates both free and fibrin-bound FXa. By this mechanism it effectively affects the clot-associated procoagulant activity which might be responsible for the propagation of intravascular thrombi as well as for recurrent thrombosis and thrombotic reocclusion after lysis. Although DX-9065a is effective after oral administration, its oral bioavailability is relatively low and seems not to be sufficient for a long-term therapeutic use of the drug. However, first clinical trials in healthy volunteers and in patients with cardiovascular diseases demonstrated a predictable pharmacokinetic and pharmacodynamic behavior of DX-9065a after either intravenous bolus injection or constant infusion, as well as its high safety, especially a lower bleeding risk compared with other commonly used drugs. Further experimental studies and ongoing clinical trials will evaluate the inhibitory profile of the drug, its effectiveness and its possible superiority over other drug regimens in various cardiovascular indications.

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Section: Effect On Fibrinolysismentioning

confidence: 69%

Section: Effect On Fibrinolysismentioning

confidence: 99%

DX‐9065a, a Direct Inhibitor of Factor Xa

Kaiser

2003

Cardiovascular Drug Reviews

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“…The effect of direct specific FXa inhibitors on fibrinolysis has not yet been studied in detail. To our knowledge, only one recent in vitro study exists comparing the effect of DX-9065a and the direct thrombin inhibitor argatroban showed that DX-9065a has no effect on the fibrinolysis and TAFI activation whereas argatroban dose-dependently accelerates fibrinolysis, and inhibits TAFI activation [124]. Since the research in this field is still very limited, it would be misleading to speculate about a potential difference between FXa and thrombin inhibitors on the regulation of fibrinolysis.…”

Section: The Role Of Fxa Inhibition In the Regulation Of Fibrinolysismentioning

confidence: 96%

Heterogeneity of Synthetic Factor Xa Inhibitors

Gerotziafas

Samama²

2005

CPD

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Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

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“…The manual assay was based on a previously described procedure developed by Nagashima [16] with some modifications [17]. In a typical experiment, FVIII-deficient plasma (75% of the final volume [f.v.]…”

Section: Fviii Concentrates and Standardsmentioning

confidence: 99%